| Publication | Description | Link |
The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State Childs, S. L.; Stahly, G. P.; Park, A. Molecular Pharmaceutics 2007, 4, 323-338 |
Salts and cocrystals are multi component crystals that can be distinguished by the location of the proton between an acid and a base. At the salt end of the spectrum proton transfer is complete, and on the opposite end proton transfer is absent in cocrystals. However, for acid-base complexes with similar pKa values, the extent of proton transfer in the solid state is not predictable and a continuum exists between the two extremes. For these systems, both the DpKa value (pKa of base D pKa of acid) and the crystalline environment determine the extent of proton transfer. A total of 20 complexes containing theophylline and guest molecules with DpKa values less than 3 have been prepared, resulting in 13 cocrystals, five salts, and two complexes with mixed ionization states based on IR spectroscopy and single-crystal diffraction data. We propose modifications to the DpKa rule for selecting salt screen counterions that focus on the discovery of solid forms with useful physical properties rather than an arbitrary cutoff value for DpKa. | Journal Link |
Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals Stahly, G.P. Crystal Growth & Design 2007, 7, 1007-1026 |
A detailed description of polymorph screening procedures is presented. On the basis of the results of 245 polymorph screens, organic compounds were found to exist in multiple solid forms quite frequently. About 90% exhibited multiple crystalline and noncrystalline forms; about 50% exhibited polymorphism. Cocrystals are defined, and cocrystal screening is discussed. Data from 64 cocrystal screens show that cocrystals were found in 61% of the cases, and the total number of cocrystals found was 192. |
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Crystal Engineering Approach To Forming Cocrystals of Amine Hydrochlorides with Organic Acids. Molecular Complexes of Fluoxetine Hydrochloride with Benzoic, Succinic, and Fumaric Acids Childs, et. al. JACS 2004, 126(41), 13335-42 |
A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors. The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride. On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water. |
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Chemical Identity Testing by Remote-Based Dispersive Raman Spectroscopy D.E. Bugay and R.C. Brush, Appl. Spectrosc. 64(5),467-475 (2010). |
The advent of robust, rugged, and current Good Manufacturing Practices (cGMP) compliant hand-held Raman spectrometers provides a wealth of opportunities for the analytical pharmaceutical chemist to bring the laboratory to the sample. This paper discusses the use of hand-held Raman spectrometers for the development of qualitative chemical identification methods for a number of well-known pharmaceutical products (tablets and capsules). Methods were developed on two different instruments and transferred to a third instrument for application of the methodology to independently obtained drug products. A novel decision algorithm is presented for the assessment of the correlation between the Raman spectrum of the unknown sample to the spectrum of the authentic reference material. This novel algorithm considers accuracy but more importantly precision (uncertainty/reliability), thus removing human bias that is associated with typical spectral searching approaches. The results presented in this paper show the reliability of developing, validating, and transferring chemical identification assays on hand-held Raman spectrometers. | Abstract Link |
| VIDEO - Detecting Adulterated Drugs - Dr. David Bugay, Triclinic Labs, Inc. | Watch the Youtube Video as Dr. Bugay discusses new technologies to detect pharmaceutical adulteration at the US Pharmacopeia Annual Meeting in 2009 | Video Link |
